Crystalline microparticles of a beta-agonist coated with a fatty acid

ABSTRACT

Crystalline microparticles consisting of a phenylalkylamino beta2-adrenergic agonist coated with a C12-C20 fatty acid are useful for the preparation of pharmaceutical aerosol formulations in form of suspension in a liquefied propellant gas or powder formulations.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to European Patent Application No.11184687.9 filed on Oct. 11, 2011, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to crystalline microparticles comprising abeta₂-agonist suitable for use in formulations to be administered byinhalation for the treatment of respiratory diseases. The presentinventions also relates to pharmaceutical aerosol formulationscomprising said microparticles and to a process for preparing them. Thepresent invention further relates to methods of treating/preventingcertain diseases and conditions by administering such microparticles.

Discussion of the Background

The administration of pharmacologically active ingredients by inhalationto the lungs is a widely used technique especially for the treatment ofreversible airway obstruction, inflammation and hyper-responsiveness.Inhalable preparations include dry powders formulations, pressurizedmetered dose (pMDI) formulations containing propellants such ashydrofluoroalkanes (HFA), or propellant-free aqueous formulations to beadministered by suitable devices such as nebulizers.

The drugs present in the formulations can either be dissolved orsuspended. A specific group of drugs administered by the pulmonary routeare bronchodilators having a local therapeutic action in the lungsand/or a systemic therapeutic action after absorption in the blood.

For example, widely used bronchodilators are beta2-agonists belonging tothe class of the phenylalkylamino derivatives such asrac-(R,R)—N-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl] phenyl]formamide, also known as formoterol.However, formoterol as well as other drugs belonging to said class maysuffer of chemical stability problems due to the susceptibility tooxidative conditions of the functional groups present on the moleculessuch as formamide and hydroxyethyl groups. Some of said groups such asformamide are also susceptive to solvolysis reactions.

On the other hand, molecules belonging to said class may also incurproblems of physical stability of their suspension formulations. This isbecause of partial solubility of the drugs in the liquefied gaspropellant. This partial solubility, in turn, may lead to an undesirableincrease in the particle size during storage and/or the formation ofaggregates.

Moreover, formulations of beta₂-agonists in HFA propellant might besusceptible to absorption of the drug into the rubber components of thevalves of the administration device. This may then cause the valves toseize resulting in a reduction of fine particle mass and/or theaggregates of particles will penetrate less well into the fine lowerrespiratory pathways, subsequently causing problems with doseuniformity.

To overcome the problems of physical stability and of adsorption of thedrug, it has been proposed in the art to coat the particles withadditives such as surfactants, and to suspend said coated particles inthe HFA propellant. For instance, WO 92/08447 and WO 91/04011 teachcoating the active agent by a process involving the steps of dissolvingthe surfactant in a solvent in which the pharmaceutically active agentis substantially insoluble, mixing a quantity of the pharmaceuticallyactive agent, in micronized form, into the surfactant solution andisolating particles of surfactant coated active agent either byfiltration and drying, or by removal of the solvent by evaporation.However, it has so far not proven possible, to manufacture usefulformulations in this way. For example, it is difficult to achieve auniform coating using techniques of this nature because the manner inwhich the surfactant agent precipitates from the evaporating solvent canbe unpredictable.

WO 2006/059152 discloses the preparation of coated particles withdispersing agents such as surfactants by mechano-fusion processes.However, it is known that particles obtained in this way are prevalentlyamorphous. On the other hand, amorphous or prevalently amorphousmaterials tend to absorb water in larger amounts than crystalline ones,and this could be a pitfall for active ingredients liable to degradationby hydrolysis.

WO 00/61108 discloses salmeterol particles coated with a surfactant andfree of any other coating excipient. They are obtained by a processinvolving the steps of suspending the active ingredient in form ofparticles in a medium, preferably water, then dispersing the surfactant,and subjecting the suspension to spray-drying. However, also in thiscase, it is well known that the use of water could yield some amorphousmaterial. Moreover, it is difficult to achieve a uniform coating if thesurfactant is dispersed and not dissolved in said medium.

WO 2008/152398 discloses particles coated with polymers such as PVPwithout any mention of their chemical stability.

US 2004/101483 discloses suspension aerosol formulations based onhydrofluoroalkanes comprising micronized particles of active ingredientsand calcium salts, magnesium salts, and zinc salts of palmitic acid andof stearic acid as solid excipients. The demonstrated advantage is thatsaid suspensions show a markedly improved valve accessibility.

US 2004/013611 discloses suspension aerosol formulations comprising atherapeutically effective amount of micronized albuterol sulfate, fromabout 5 to 15 percent by weight of ethanol, from about 0.05 to about 0.5percent by weight of a surfactant selected from the group consisting ofoleic acid and sorbitan trioleate, and HFC 227 as substantially the onlypropellant. Said formulations are characterized in that they exhibitsubstantially no growth in particle size or change in crystal morphologyof the drug over a prolonged period, are substantially and readilyredispersible, and upon redispersion do not flocculate so quickly as toprevent reproducible dosing of the drug. Nothing is said about theirchemical stability.

In view of the above, there is still a need for particles ofbeta₂-agonists of high chemical stability as well as being capable ofgiving rise to physically stable suspensions with a slow sedimentationrate and a reduced adhesion to the components of the device. Theseproblems are solved by the particles of the present invention.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelparticles of beta₂-agonists.

It is another object of the present invention to provide novelbeta₂-agonists which exhibit high chemical stability.

It is another object of the present invention to provide novelbeta₂-agonists which are capable of giving rise to physically stablesuspensions with a slow sedimentation rate and a reduced adhesion to thecomponents of a device in which they are contained.

It is another object of the present invention to provide novel methodsof preparing such particles.

It is another object of the present invention to provide novel methodsof treating and/or preventing certain diseases and conditions byadministering such particles.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discovery ofcrystalline microparticles consisting of a phenylalkylaminobeta₂-adrenergic agonist coated with a C12-C20 fatty acid in an amountcomprised between 0.2 and 2.5% by weight.

Thus, in a first aspect, the invention is directed to crystallinemicroparticles comprising a phenylalkylamino beta₂-adrenergic agonistcoated with a C12-C20 fatty acid in an amount comprised between 0.2 and2.5% by weight.

In a second aspect, the crystalline microparticles preferably consist ofa phenylalkylamino beta₂-adrenergic agonist coated with a C12-C20 fattyacid in an amount comprised between 0.2 and 2.5% by weight.

Advantageously, said beta₂-agonist is selected from a derivativebelonging to the general formula (I):

wherein

R₁ is CH₂OH or NHCOR₁₀

with the proviso that, when R₁ is CH₂OH, R₂ is hydrogen, while, when R₁is NHCOR₁₀, R₂ and R₁₀ can be independently hydrogen or form together avinylene (—CH═CH—) or ethoxy (—CH₂—O—) radical;

m is an integer from 0 to 5, preferably 0 or 5;

n is an integer from 0 to 4, preferably 0, 2 or 4;

p is an integer from 0 to 2, preferably 0 or 1;

A represents oxygen or a bond;

B represents oxygen or a bond;

R₃ and R₄ are hydrogen or methyl; otherwise, when m is 1, n, p are 0, Aand B are bonds, and R₃ is hydrogen, R₄ can form with R₅ a methylenebridge —(CH₂)q- where q is 1 or 2, preferably 1;

R₅, R₆, R₇, R₈, and R₉, which are the same or different, are eachindependently selected from hydrogen, hydroxyl, C₁-C₄ alkyl, C₁-C₄alkoxy, halogen atoms, SO₂NH₂, and 2-hydroxy-2-phenyl-ethylamino;preferably they are hydrogen, halogen atoms, C₁-C₄ alkyl, and C₁-C₄alkoxy,

and pharmaceutically acceptable salts and/or solvates thereof.

In a third aspect, the invention provides pharmaceutical aerosolformulations for pressurized metered dose inhalers (pMDIs) comprisingthe above microparticles in suspension in a liquefied propellant gas.

In a fourth aspect, the invention provides pressurized metered doseinhalers (pMDI) comprising a canister filled with the aforementionedaerosol pharmaceutical formulation, and a metering valve for deliveringa daily therapeutically effective dose of the active ingredient.

In a fifth aspect, the invention concerns dry powder pharmaceuticalformulations comprising the above microparticles and, optionally acarrier.

In a sixth aspect, the invention provides dry powder inhalers filledwith the aforementioned dry powder formulation.

In a seventh aspect, the present invention is directed to a process forpreparing the microparticles of the invention, said process comprisingthe steps of:

(a) preparing a solution of the C12-C20 fatty acid in a fluorinatedmodel propellant wherein the beta₂-agonist is substantially insolubleselected from the group of perfluoropentane, 2H,3H-perfluoropentane(HPFP), perfluorohexane, and 1H-perfluorohexane;

(b) adding the micronized drug powder to the solution of the fatty acid;

(c) stirring to give a homogeneous suspension; and

(d) subjecting the resulting suspension to spray-drying to obtain thecoated microparticles.

In an eighth aspect, the present invention is also directed to themicroparticles of the invention for use for the prevention and/ortreatment of a respiratory disease.

In an ninth aspect, the present invention is further directed to the useof the microparticles of the invention in the manufacture of amedicament for the prevention and/or treatment of a respiratory disease.

In a tenth aspect, the present invention provides methods for preventingand/or treating a respiratory disease in a patient, comprisingadministering a therapeutically effective amount of the microparticlesof the invention.

In an eleventh aspect, the present invention concerns crystallinemicroparticles consisting of a phenylalkylamino beta₂-adrenergic agonistcoated with a C12-C20 fatty acid in an amount comprised between 0.2 and2.5% by weight, said microparticles obtainable by a process comprisingthe steps of:

(a) preparing a solution of the C12-C20 fatty acid in a fluorinatedmodel propellant wherein the beta₂-agonist is substantially insolubleselected from the group of perfluoropentane, 2H,3H-perfluoropentane(HPFP), perfluorohexane, and 1H-perfluorohexane;

(b) adding the micronized drug powder to the solution of the fatty acid;

(c) stirring to give a homogeneous suspension; and

(d) subjecting the resulting suspension to spray-drying to obtain thecoated microparticles.

In a further aspect, the present invention provides a process forpreparing crystalline microparticles consisting of a drug to beadministered by inhalation coated with a C12-C20 fatty acid, saidprocess comprising the steps of:

(a) preparing a solution of the C12-C20 fatty acid in a fluorinatedmodel propellant wherein the drug is substantially insoluble selectedfrom the group of perfluoropentane,

2H,3H-perfluoropentane (HPFP), perfluorohexane, and 1H-perfluorohexane;

(b) adding the micronized drug powder to the solution of the fatty acid;

(c) stirring to give a homogeneous suspension; and

(d) subjecting the resulting suspension to spray-drying to obtain thecoated microparticles.

The invention is also directed to the crystalline coated microparticlesobtainable by said process.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same become betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawings, wherein:

FIG. 1 is a thermogram of microparticles of the present invention incomparison to crystalline microparticles of formoterol fumaratedihydrate (top line).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The term “halogen atoms” as used herein includes fluorine, chlorine,bromine and iodine.

The expression “C₁-C₄ alkyl” refers to straight-chained and branchedalkyl groups wherein the number of carbon atoms is in the range 1 to 4.Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl andt-butyl, preferably methyl and ethyl.

The expression “C₁-C₄ alkoxy” refers to straight and branched chainalkoxy groups wherein the number of carbon atoms is in the range 1 to 4.Exemplary groups are methoxy, ethoxy, and butyloxy.

The term “coated’ refers to microparticles having their surface coveredby a continuous film of the fatty acid.

The term “single therapeutically effective dose” means the quantity ofactive ingredient administered at one time by inhalation upon actuationof the pMDI or DPI inhaler.

Said dose may be delivered in one or more actuations, preferably oneactuation (shot) of the inhaler.

The term “actuation” refers to the release of active ingredient from thedevice by a single activation (e.g. mechanical or breath).

For “fluorinated model propellant” it is meant a fluorinated alkanederivative liquid at room temperature and at atmospheric pressure inwhich common beta₂-agonists are insoluble. Typical members of this classare perfluoropentane, 2H,3H-perfluoropentane, perfluorohexane, and1H-perfluorohexane. 2H,3H-perfluoropentane is also known as HPFP (seeRogueda P. Drug Dev. Ind. Pharm., 2003, 29(1), 39-49, which isincorporated herein by reference in its entirety).

“Substantially insoluble” refers to an active ingredient having asolubility in the desired medium of less than 1.0% w/v, preferably ofless than 0.5%, more preferably less than 0.1% w/v.

In general terms, the particle size of the particles is quantified bymeasuring a characteristic equivalent sphere diameter, known as volumediameter, by laser diffraction. The particle size can also be quantifiedby measuring the mass diameter by means of suitable instruments andtechniques known to the skilled person, such as sieving.

The volume diameter (VD) is related to the mass diameter (MD) by thedensity of the particles (assuming the size being independent from thedensity of the particles).

In the present application, the particle size interval is expressed interms of mass diameter. Otherwise, the particle size distribution isexpressed in terms of: i) the volume median diameter (VMD) whichcorresponds to the diameter of 50 percent by weight or volumerespectively, of the particles, e.g. d(v0.5), and ii) the volumediameter (VD) in microns of 10% and 90% of the particles, respectively,e.g. d(v0.1) and d(v0.9).

Upon aerosolization, the particle size is expressed as mass aerodynamicdiameter (MAD) and the particle size distribution as mass medianaerodynamic diameter (MMAD). The MAD indicates the capability of theparticles of being transported as suspended in an air stream. The MMADcorresponds to the mass aerodynamic diameter of 50 percent by weight ofthe particles.

The expression “physically stable” refers to formulations which exhibitsubstantially no growth in particle size or change in crystal morphologyof the suspended particles over a prolonged period, are readilyredispersible, and upon redispersion, do not flocculate so quickly as toprevent reproducing dosing of the active ingredient.

The expression “chemically stable” refers to a formulation that, uponstorage, meets the requirements of the EMEA Guideline CPMP/QWP/122/02referring to “Stability Testing of Existing Active Substances andRelated Finished Products”.

The expression “respirable fraction” refers to an index of thepercentage of active particles which would reach the deep lungs in apatient.

The respirable fraction, also termed fine particle fraction (FPF), isevaluated using a suitable in vitro apparata such as Next GenerationImpactor (NGI), Multistage Cascade Impactor or Multi Stage LiquidImpinger (MLSI) according to procedures reported in commonPharmacopoeias. It is calculated by the ratio between the delivered doseand the fine particle mass (formerly fine particle dose).

The delivered dose is calculated from the cumulative deposition in theapparatus, while the fine particle mass is calculated from thedeposition on Stage N (herein N is an integer number) to filter (AF)corresponding to particles ≤5.0 microns.

The term “therapeutically effective amount” means the amount of activeingredient that, when delivered to the lungs, provides the desiredbiological effect.

The term “prevention” means an approach for reducing the risk of onsetof a disease.

The term “treatment” means an approach for obtaining beneficial ordesired results, including clinical results. Beneficial or desiredclinical results can include, but are not limited to, alleviation oramelioration of one or more symptoms or conditions, diminishment ofextent of disease, stabilized (i.e. not worsening) state of disease,preventing spread of disease, delay or slowing of disease progression,amelioration or palliation of the disease state, and remission (whetherpartial or total), whether detectable or undetectable.

The present invention concerns crystalline microparticles comprising orconsisting of a phenylalkylamino beta₂-adrenergic agonist andpharmaceutically acceptable salts and/or solvates thereof.

Phenylalkylamino beta₂-adrenergic agonists are drugs having abronchodilator activity and include for example salbutamol (albuterol),bambuterol fenoterol, procaterol, salmeterol, indacaterol, andformoterol.

Pharmaceutically acceptable salts include those obtained by reacting theamino group of the compound with an inorganic or organic acid to form asalt, for example, hydrochloride, hydrobromide, sulphate, phosphate,methane sulfonate, camphor sulfonate, oxalate, maleate, fumarate,succinate, citrate, cinnamate, xinafoate, and trifenatate.

Advantageously, said beta₂-agonist is selected from a derivativebelonging to the general formula (I).

The compounds of general formula (I) may contain asymmetric centers.

Therefore the present invention includes all the optical stereoisomersand mixtures thereof.

A first class of preferred compounds is that wherein

R₁ is NHCOR₁₀ with R₁₀═H, R₄ is methyl, m is 1, n, p are 0, A and B arebonds, R₃, R₅, R₆, R₈ and R₉ are H, and R₇ is methoxy.

When the phenolic group is adjacent to R₁, the compound is known asformoterol.

As it contains two chiral centers, formoterol is preferably used in theform of 1:1 (R,R), (S,S) racemate or (R,R) enantiomer, more preferablyas the racemate.

A particularly preferred salt is the fumarate dihydrate.

A second class of preferred compounds is that wherein:

R₁ is NHCOR₁₀ wherein R₁₀ forms together with R₂ a vinylene (—CH═CH—)radical, R₄ is H, R₃ forms with R₅ a methylene bridge —(CH₂)q- with q=1,m is 1, n, p are 0, A and B are bonds, R6 and R₉ are H and R₇ and R₈ areethyl group.

When the phenolic group is adjacent to R₁, the compound is known asindacaterol.

Since it contains a chiral center, indacaterol is preferably used in theform of R-enantiomer, more preferably as maleate salt.

A third class of preferred compounds is that wherein:

R₁ is CH₂OH, R₂ R₆, R₇ and R₈ are H, R₅ and R₉ are chlorine atoms, A andB are O, m is 5, n is 2, and p is 1.

When the phenolic group is adjacent to R₁, the compound is known asvilanterol. Vilanterol is preferably used in the form of R-enantiomer astrifenatate salt

A fourth class of preferred compounds is that wherein:

R₁ is NHCOR₁₀ with R₁₀ forming together with R₂ an ethoxy (—CH2-O—)radical, R₃ and R₄ are methyl, m=1, A d B are bonds, n and p are 0, R₅,R₆, R₈ and R₉ are H, and R₇ is methoxy. When the phenolic group is metato R₁ the compound is known as olodaterol, that is preferably used asR-enantiomer.

A fifth class of preferred compounds is that wherein:

R₁ is NHCOR₁₀ with R₁₀═H, R₂, R₃, R₄, R₅, R₆, R₈ and R₉ are H, m is 1, Aand B are bonds, n and p are 0, and R₇ is 2-hydroxy-2-phenyl-ethylamino.

When the phenolic group is adjacent to R, the compound is known asmilveterol. As it contains two chiral centers, milveterol is preferablyused in the form of (R,R)-enantiomer, more preferably as thehydrochloride salt.

A sixth class of preferred compounds is that wherein:

R₁ is CH₂OH, R₂, R₃, R₄, R₅, R₆, R₈ and R₉ are H, m is 5, n is 4, p is0, A is O, and B is a bond.

When the phenolic group is adjacent to R₁ the compound is known assalmeterol. As it contains one chiral center, salmeterol is preferablyused in the form of racemic form (R,S), more preferably as a xinafoatesalt.

Preferably, the compound of formula (I) is a long-acting beta₂-agonistselected from the group consisting of formoterol, salmeterol,vilanterol, olodaterol, milveterol, indacaterol, and pharmaceuticallyacceptable salts and/or solvates thereof.

In a particular embodiment, preferred compounds are those wherein R₁ isNHCOR₁₀, R₂ and R₁₀ are H, and the other substituents and indexes havethe meanings reported above.

In fact, phenylalkylamino derivatives bearing said group areparticularly sensitive to solvolysis reactions.

The preferred compound of said class is formoterol, preferably in theform of fumarate dihydrate salt.

In another particular embodiment, preferred compounds are those whereinR₁CH₂OH, R₂ is H, and the other substituents and indexes have themeanings reported above.

The preferred compound of said class is salmeterol, preferably in theform of a xinafoate salt.

The particle size of said microparticles is lower than 15 microns,preferably lower than 10 microns. Advantageously, at least 90% of theparticles have a volume diameter lower than about 5 micron. Moreadvantageously no more than 10% of the microparticles have a volumediameter [d(v,0.1)] lower than 0.6 micron, and no more than 50% ofparticles have a volume diameter [d(v,0.5)] lower than 1.5 micron.

Preferably the [d(v,0.5)] is comprised between 1.5 and 3.0 micron.

The particle size method could be measured by laser diffractionaccording to known methods.

The microparticles of the compound of general formula (I) are coatedwith a C12-C20 fatty acid in an amount comprised between 0.2 and 2.5% byweight of said particles, preferably between 0.5 and 2.0% by weight. Inone embodiment, the preferred amount may be comprised between 1.0 and2.0% by weight, while in other embodiment, it may be comprised between0.5 and 1.0% by weight.

The C12-C20 fatty acid is advantageously selected from the groupconsisting of saturated and monounsaturated compounds such as lauricacid (C12:0), myristic acid (C14:0), palmitic acid (C16:0), palmitoleicacid (C16:1), stearic acid (C18:0), oleic acid (C18:1), and arachidicacid (C20:0) or mixtures thereof.

More preferably, the fatty acid it is a saturated fatty acid selectedfrom the group consisting of myristic acid, palmitic acid, stearic acid,and arachidic acid. In a preferred embodiment, the fatty acid ismyristic acid. In fact, the percentage being equal, myristic acid iscapable of giving rise to higher performances in terms of respirablefraction (FPF) as it can be appreciated from the Examples.

As monounsaturated acid, oleic acid may be preferably used.

The fatty acid shall form a continuous film on the surface of themicroparticles.

Depending on the amount of fatty acid, the coating may cover part of themicroparticles or all of them (complete coating), preferably all ofthem.

The amount of beta₂-adrenergic agonist will depend on its singletherapeutically effective dose, which in turn, depends on the kind andthe severity of the disease and the conditions (weight, sex, age) of thepatient.

For example, in the case of formoterol, the single therapeuticallyeffective dose could be 6 or 12 μg, calculated as fumarate dihydratesalt.

Once the microparticles of the invention are suspended in a liquefiedpropellant gas, the relevant suspensions turned out to be chemically andphysically stable over time and capable of giving rise to excellentrespirable fraction. Unexpectedly, said formulations show a lowersedimentation speed than the corresponding formulations comprisinguncoated microparticles.

Accordingly, the present invention provides for pressurized metered doseinhalers (pMDIs) comprising the above microparticles in suspension in aliquefied propellant gas.

Any liquefied propellant gas may be used, preferably a hydrofluoroalkane(HFA) propellant. Advantageously, the liquefied propellant gas is1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or1,1,1,2-tetrafluoroethane (HFA 134a), and mixtures thereof.

The formulations of the present invention may also comprise otherpharmaceutically acceptable excipients, for instance surfactants.Suitable surfactants are known in the art and include: sorbitan esterssuch as sorbitan trioleate, sorbitan monolaurate, sorbitan mono-oleateand their ethoxylated derivates such as polysorbate 20, polysorbate 80;ethylene oxide/propylene oxide co-polymers and other agents such asnatural or synthetic lecithin, oleic acid, polyvinylpyrrolidone (PVP),and polyvinyl alcohol.

The amount of surfactant, which may be present in the pMDI formulationaccording to the invention, is usually in the range of 0.001 to 3.0%(w/w), preferably between 0.005 to 1.0% (w/w).

The formulations according to the present invention may further compriseother active ingredients useful for the prevention and/or treatment ofrespiratory diseases, for instance corticosteroids or antimuscarinicdrugs suspended or dissolved in the liquefied propellant gas.

Examples of corticosteroids are beclometasone dipropionate (BDP),fluticasone propionate, fluticasone furoate, mometasone furoate,budesonide, and ciclesonide.

Examples of antimuscarinic drugs are ipratropium bromide, tiotropiumbromide, glycopyrronium bromide, and aclidinium bromide.

According to another aspect, the present invention provides a pMDIcomprising a canister filled with the pharmaceutical formulation of theinvention and a metering valve for delivering a daily therapeuticallyeffective dose of the active ingredient.

The aerosol formulation according to the invention shall be filled intopMDIs.

Said pMDIs comprise a canister fitted with a metering valve. Actuationof the metering valve allows a small portion of the spray product to bereleased.

Part or all of the internal surfaces of the canister may be made ofglass or of a metal, for example aluminum or stainless steel or anodizedaluminum.

Alternatively the metal canister may have part or all of the internalsurfaces lined with an inert organic coating. Examples of preferredcoatings are epoxy-phenol resins, perfluorinated polymers such asperfluoroalkoxyalkanes, perfluoroalkoxyalkylenes, perfluoroalkylenessuch as poly-tetrafluoroethylene (Teflon),fluorinated-ethylene-propylene, polyether sulfone,fluorinated-ethylene-propylene (FEP), and fluorinated-ethylene-propylenepolyether sulfone (FEP-PES) mixtures or combination thereof. Othersuitable coatings may be polyamide, polyimide, polyamideimide,polyphenylene sulfide or their combinations.

The canister is closed with a metering valve for delivering a dailytherapeutically effective dose of the active ingredient.

Generally, the metering valve assembly comprises a ferrule having anaperture formed therein, a body molding attached to the ferrule whichhouses the metering chamber, a stem constituted of a core and a coreextension, an inner- and an outer seal around the metering chamber, aspring around the core, and a gasket to prevent leakage of propellantthrough the valve.

The gasket may comprise any suitable elastomeric material such as, forexample, low density polyethylene, chlorobutyl, black and whitebutadiene-acrylonitrile rubbers, butyl rubber, neoprene, EPDM (a polymerof ethylenepropylenediene monomer) and TPE (thermoplastic elastomer).EPDM rubbers are particularly preferred.

Suitable valves are commercially available from manufacturers well knownin the aerosol industry, for example, from Valois, France, Bespak, plcUK and 3M, Neotechnic Ltd UK.

The formulation shall be actuated by a metering valve capable ofdelivering a volume of between 25 μl and 100 μl, e.g. 25 μl, 50 μl, 63μl or 100 μl.

Advantageously, the MDI device filled with the formulation may beequipped with a dose counter.

Surprisingly, when administered as a powder by a suitable device, themicroparticles of the inventions give rise to a significantly higherrespirable fraction than the corresponding uncoated microparticles.

Accordingly, the invention also provides a dry powder pharmaceuticalformulation comprising the above microparticles and optionally acarrier.

The carrier particles may be made of any physiologically acceptable,pharmacologically inert material or combination of materials suitablefor inhalatory use. For example, the carrier particles may be composedof one or more materials selected from sugar alcohols; polyols, forexample sorbitol, mannitol and xylitol, and crystalline sugars,including monosaccharides and disaccharides.

Preferably, the carrier particles are made of lactose, more preferablyof alpha-lactose monohydrate.

Advantageously, said carrier particles have a mass diameter (MD) of atleast 50 microns, more advantageously greater that 90 microns.Preferably the MD is comprised between 50 microns and 500 microns.

In certain embodiments of the invention, the MD may be comprised between90 and 150 microns.

In other embodiments, the MD may be comprised between 150 and 400micron, with a MMD preferably greater than 175 microns, and morepreferably the MD may be comprised between 210 and 355 microns.

The desired particle size may be obtained by sieving according to knownmethods.

The aforementioned powder formulation may also advantageously comprisean additive material, preferably bound to the surface of the carrierparticles. Said additive material may be an amino acid, preferablyselected from leucine or isoleucine, or a water soluble surface activematerial, for example lecithin, in particular soya lecithin, or alubricant selected from the group consisting of stearic acid and saltsthereof such as magnesium stearate, sodium lauryl sulphate, sodiumstearyl fumarate, and stearyl alcohol.

The dry powder formulations herein described may be used in allcustomary dry powder inhalers, such as unit dose or multidose inhalers.

For example, said formulations may be filled in hard gelatine capsules,in turn loaded in a unit dose inhaler such as the Aerolizer™ or theRS01/7 model available from Plastiape, Italy.

Alternatively, it may be filled in a multidose inhaler comprising apowder reservoir as described in WO 2004/012801, which is incorporatedherein by reference in its entirety.

The present invention further provides a process for preparing themicroparticles of the invention, said process comprising the steps of:

-   -   (a) preparing a solution of the C12-C20 fatty acid in a        fluorinated model propellant wherein the beta2-agonist is        substantially insoluble selected from the group of        perfluoropentane, 2H,3H-perfluoropentane (HPFP),        perfluorohexane, and 1H-perfluorohexane;    -   (b) adding the micronized drug powder to the solution of the        fatty acid;    -   (c) mixing to give a homogeneous suspension; and    -   (d) subjecting the resulting suspension to spray-drying to        obtain the coated microparticles.

It fact, it has been found that, due to the physico-chemical propertiesof the utilized model propellant, the solid characteristic of theparticles upon drying are not modified, and they remain substantiallycrystalline. Advantageously, the microparticles of the present inventionhave a crystalline degree, expressed as weight % of the crystallinecompound with respect to the total weight of the compound, of at least90%, preferably of at least 95%, even more preferably of at least 98%,determined according to methods know in the art such as differentialscanning calorimetry (DSC), microcalorimetry or X-ray powderdiffractometry.

Moreover, since the fatty acid is added as a solution, a uniform andextensive coating of microparticles is achieved. Said coating with thefatty acid is performed in the absence of any other coating excipient.

Without being limited by the theory, said uniform and extensive coatingmay contribute to improve the chemical stability of the activeingredient. Furthermore, it prevents both the partial solubilization andformation of aggregates of the drug, once suspended in a liquefiedpropellant gas, making possible to obtain formulations characterized byan improved physical stability.

It is believed that the features of the coating explain the betterinhalatory performances of the microparticles of the invention, onceadministered as a powder, in comparison to the uncoated microparticles.

The fluorinated model propellant shall be selected depending on thesolubility characteristics of both the active ingredient and the fattyacid.

Preferably, said model propellant is perfluoropentane or2H,3H-perfluoropentane (HPFP), more preferably 2H,3H-perfluoropentane.

The amount of the fatty acid in the solution will vary depending on theamount of active ingredient added in stage (b) and will be selected soas to obtain a percentage in the final coated microparticles comprisedbetween 0.2 and 2.5% by weight.

The content of the active ingredient in the suspension prepared in stage(b) can vary within wide limits, usually within the range from 1 to 40%w/v, preferably from 2 to 20% w/v, more preferably from 5 to 10% w/v.

In said stage, the micronized drug powder may be added to the solutionof the fatty acid and then mixed with techniques known in the art, e.g.sonicating or stirring, to give a homogeneous suspension (stage (c).

In stage (d), the obtained suspension, maintained under stirring, issubjected to spray drying in an appropriate apparatus.

The operating parameters of the apparatus, such as the flow rate of thesuspension arriving in the drying chamber, the size of the nozzle, theinlet and outlet temperature, the atomizing pressure and the flow rateof the atomizing air, may be adjusted by any skilled person according tothe recommendations of the manufacturer.

A suitable spray dryer is, for example, the Büchi 191 Mini Spray Dryer(Büchi Company, Switzerland).

Typical parameters are the following:

inlet air temperature: 60 to 150° C., preferably 95 to 105° C., morepreferably 100° C.;

outlet temperature: 40 to 110° C., preferably 55 to 65° C., morepreferably 60° C.;

air flow rate: 600 l/h;

feed flow: 4 ml/min; and

nozzle diameter: 0.7 mm.

Once collected, the microparticles have a diameter less than 15 micron.

Optionally, they may be subjected to conventional milling techniques toadjust their size.

Administration of the microparticles of the invention may be indicatedfor prevention and/or the treatment of mild, moderate or severe acute orchronic symptoms or for prophylactic treatment of an inflammatory orobstructive airways disease such as asthma and chronic obstructivepulmonary disease (COPD).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1. Preparation of Microparticles of Formoterol FumarateAccording to the Invention

5 mg of myristic acid were dissolved in 100 ml of 2H,3H-perfluoropentaneat 30-35° C. in a water bath. 995 mg of formoterol fumarate dihydrate asmicronized particles were added and dispersed, the suspension wassonicated and then kept under stirring. The suspension thus obtainedcontained 99.5% formoterol fumarate dihydrate and 0.5% myristic acid byweight.

This suspension was spray-dried in a Büchi 191 Mini Spray Dryer usingthe following parameters:

inlet air temperature: 100° C.;

outlet temperature: 60° C.;

air flow rate: 600 l/h;

feed flow: 4 ml/min; and

nozzle diameter: 0.7 mm.

The yield of the process was 69.0%.

Analogously, formoterol fumarate dehydrate (FF) microparticles havingthe following compositions were obtained:

FF Yield Sample (w/w %) Additive (w/w %) (%) FF-myr 1.0% 99.0 Myristicacid 1.0 70.3 FF-myr 2.0% 98.0 Myristic acid 2.0 68.1 FF-lau 0.5% 99.5Lauric acid 0.5 68.4 FF-pal 0.5% 99.5 Palmitic acid 0.5 69.3 FF-ole 0.5%99.5 Oleic acid 0.5 69.3

Example 2. Characterization of the Microparticles of Example 1

The microparticles as obtained in Example 1 were subjected to thefollowing analysis.

Scanning electron microscopy (SEM). Morphological properties wereinvestigated using a scanning electron microscope (SEM, Zeiss SUPRA 40,Oberkochen, Germany). Each sample was carefully mounted on a sampleholder, so as to ensure representative images, and analyzed withoutcoating sputter. SEM micrographs were taken using in-built image capturesoftware. The obtained images demonstrate that the microparticles of theinvention do not change their morphological aspect in comparison to theuncoated FF microparticles.

Differential scanning calorimetry (DSC). The crystalline properties werefurther investigated by differential scanning calorimetry (DSC). Thedata were obtained on a Mettler Toledo Instrument DSC821c, softwareSTARe. The calibration standard used is indium. Approximately 2 to 5 mgof a sample is placed into a DSC pan, and the weight is accuratelymeasured and recorded. The pan is hermetically sealed. The sample isheated under nitrogen at a rate of 20° C./min, from 25° C. to a finaltemperature of 200° C. The thermogram reported in FIG. 1 shows that thecharacteristic endothermic transition ending at about 160° C., typicalof crystalline formoterol fumarate dihydrate, is still present in themicroparticles of the invention, indicating that the spray-dryingprocess has not modified the solid characteristics of the drug.

The microparticles coated with amounts of additive ranging from 1.0 to2.0% w/v are more crystalline than microparticles coated with a loweramount, i.e. 0.5% w/v.

Particle size via laser diffraction. Particle size distributions weremeasured by laser diffraction (Spraytec®S, Malvern Instruments,Worcestershire, UK). The powders were dispersed in Span85:cyclohexane0.1% w/v. The results are reported in Table 1. After spray-drying, theparticle size of the microparticles of the invention does notsubstantially change in comparison to that of raw formoterol fumaratedihydrate.

TABLE 1 Particle size d(v0.1) d(v0.5) d(v0.9) Sample (μm) (μm) (μm) FFraw material 0.62 1.69 3.27 FF-lau 0.5 0.86 1.96 3.60 FF-myr 0.5 0.961.65 2.46 FF-pal 0.5 0.85 1.84 3.48 FF-ole 0.5 0.82 1.78 3.56

Example 3. pMDI Formulation Comprising the Microparticles of Example 1

To prepare pMDI aerosol suspension formulations with a nominal dose ofthe active ingredient of 12 μg, the aluminum canisters were filled in acontrolled atmosphere room, by successively introducing 2.4 mg themicroparticles of Example 1 and then 10 ml pressurized HFA134a gas. Thedevices were fitted with a 50 μl APTAR valve and a Bespak actuator of0.3 mm. For comparative purposes, a pMDI aerosol suspension formulationscomprising micronized formoterol fumarate dihydrate was also prepared.The sedimentation rate was determined using a Turbiscan apparatus(Formulaction SA, France).

The pMDI formulations obtained with microparticles of the inventionexhibit a good homogenous distribution of the suspended particles aswell as a higher level of physical stability than the comparativeformulation, as the particles sediment more slowly and are less liableto form agglomerates.

The pMDI formulations were also characterized in terms of aerosolperformances. They were assessed using a Next Generation Impactor toaccording to the procedure described in the European Pharmacopoeia7^(th) edition, 2011, part 2.9.18.

Quantification of formoterol fumarate dihydrate (FF) was performed usinga HPLC method. The following parameters were determined:

-   -   i) delivered dose (DD) is calculated from the cumulative        deposition in the ACI, divided by the number of actuations per        experiment;    -   ii) fine particle mass (FPM) is obtained by interpolation of the        cumulative percentage undersize of drug mass deposition versus        cut off diameter. The FPM corresponds to particles of diameter        ≤5.0 microns, divided by the number of actuations per        experiment.    -   iii) respirable fraction (fine particle fraction=FPF) which is        the percent ratio between the fine particle mass and the        delivered dose.    -   iv) mass median aerodynamic diameter (MMAD) which is the        diameter around which the mass aerodynamic diameters of the        emitted particles are distributed equally;

The results (as a mean±S.D.) are summarized in Table 2. It is evidentthat the PMDI formulations comprising the microparticles of theinvention give rise to an excellent respirable fraction, comparable tothat of the formulation comprising uncoated micronized FF.

TABLE 2 Aerosol performances of the pMDI formulations. MMAD Sample DD(μg) (μm) FPM (μg) FPF (%) FF-Raw 8.34 ± 0.32 1.92 ± 0.00 6.84 ± 0.5181.9 ± 2.9 FF-Lau 0.5 7.10 ± 0.22 2.07 ± 0.13 5.35 ± 0.11 75.4 ± 0.8FF-Pal 0.5 8.12 ± 0.35 2.20 ± 0.01 6.30 ± 0.14 77.7 ± 1.6 FF-Ole 0.58.56 ± 0.33 2.10 ± 0.10 6.85 ± 0.42 80.1 ± 1.8 FF-Mir0.5 8.23 ± 0.232.45 ± 0.01 5.12 ± 0.21 62.2 ± 0.7 FF-Mir 1 8.21 ± 0.25 2.18 ± 0.08 6.46± 0.39 78.7 ± 2.3 FF-Mir 2 8.69 ± 0.07 2.05 ± 0.03 7.31 ± 0.02 84.1 ±0.5

Example 4. Powder Formulation Comprising Formoterol FumarateMicroparticles According to the Invention

To prepare powder formulations, the microparticles of Example 1 FF-myr0.5 and Ff-myr 2.0 were mixed in a Turbula mixer with alpha-lactosemonohydrate having a mass diameter comprised between 90 and 150 m as acarrier, to obtain a ratio of 6 μg of drug to 10 mg of carrier. Forcomparative purposes, a powder formulation comprising micronizedformoterol fumarate dihydrate was also prepared. Each powder was filledin hard HMPC gelatine capsules, in turn loaded in a RS01/7 unit doseinhaler (Plastiape, Italy).

The aerosol performances were evaluated using a Next Generation Impactor(NGI) according to the procedure described in European Pharmacopoeia7^(th) edition, 2011, part 2.9.18, pages 281-285. The results(mean±S.D.) in terms of delivered dose (DD), fine particle mass (FPM),fine particle fraction (FPF) and mass median aerodynamic diameter(MMAD), are reported in Table 3. The data demonstrate that the powderformulations comprising the microparticles of the invention give rise tosignificantly higher respirable fractions than that comprising uncoatedmicronized FF.

TABLE 3 Aerosol performances of the powder formulations FPF Sample DD μgFPM μg % MMAD μm FF-raw 4  73 ± 0.02 0.71 ± 0.04 14.03 ± 0.82 2.36 ±0.05 FF-myr 0.5 4.41 ± 0.01 1.17 ± 0.04 26.47 ± 1.02 1.85 ± 0.03 FF-myr2.0 4.69 ± 0.30 1.09 ± 0.06 23.35 ± 0.25 1.65 ± 0.02

Example 5. Preparation of Microparticles of Salmeterol XinafoateAccording to the Invention

10 mg of myristic acid were dissolved in 100 ml of2H,3H-perfluoropentane at 30-35° C. in a water bath, 990 mg ofsalmeterol xinafoate (SX) as micronized particles were added anddispersed, the suspension was sonicated and then kept under stirring.The suspension thus obtained contained 99% formoterol fumarate dihydrateand 1.0% myristic acid by weight. This suspension was spray-dried in aBüchi 191 Mini Spray Dryer with the following parameters:

inlet air temperature: 100° C.;

outlet temperature: 64° C.;

air flow rate: 600 l/h;

feed flow: 4 ml/min; and

nozzle diameter: 0.7 mm.

Analogously, SX microparticles with oleic acid were prepared. Themicroparticles have the following composition:

FF Yield Sample (w/w %) Additive (w/w %) (%) SX-myr 1.0% 99.0 Myristicacid 1.0 75.0 SX-ole 2.0% 98.0 Oleic acid 1.0 85.0

Example 6. pMDI Formulation Comprising the Microparticles of Example 5

To prepare pMDI aerosol suspension formulations with a nominal dose ofthe active ingredient of 25 μg, canisters coated with FEP were filled ina controlled atmosphere room, by successively introducing 3.0 mg themicroparticles of Example 5 and then 6 ml pressurized HFA134a gas. Thedevices were fitted with a 50 μl APTAR valve and a Bespak actuator of0.3 mm. For comparative purposes, a pMDI aerosol suspension formulationscomprising micronized salmeterol xinafoate was also prepared. The pMDIformulations were characterized in terms of aerosol performances. Theywere assessed as described in Example 3. The results (as a mean+S.D.)are summarized in Table 4.

It is evident that the PMDI formulations comprising the microparticlesof the invention give rise to a satisfactory respirable fraction,slightly better to that of the formulation comprising uncoatedmicronized,

TABLE 4 Aerosol performances of the pMDI formulations Sample DD μg FPMμg FPF % MMAD μm SX raw 14.28 ± 1.72 4.23 ± 0.25 29.74 ± 1.75 2.79 ±0.39 SX-ole 1.0 16.73 ± 2.09 5.82 ± 0.83 34.77 ± 2.32 3.02 ± 0.06 SX-myr1.0 22.43 ± .76 6.77 ± 0.57 39.55 ± 4.06 2.46 ± 0.07

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

1. Crystalline microparticles, comprising a phenylalkylaminobeta₂-adrenergic agonist coated with at least one C12-C20 fatty acid inan amount of 0.2 to 2.5% by weight based on the weight of saidmicroparticles.
 2. Crystalline microparticles according to claim 1,which consist of a phenylalkylamino beta₂-adrenergic agonist coated withat least one C12-C20 fatty acid in an amount of 0.2 to 2.5% by weightbased on the weight of said microparticles.
 3. Crystallinemicroparticles according to claim 1, wherein said beta₂-agonist is acompound of formula (I):

wherein R₁ is CH₂OH or NHCOR₁₀ with the proviso that, when R₁ is CH₂OH,R₂ is always hydrogen, while, when R₁ is NHCOR₁₀, R₂ and R₁₀ can beindependently hydrogen or form together a vinylene (—CH═CHμ) or ethoxy(—CH₂—O—) radical; m is an integer from 0 to 5; n is an integer from 0to 4; p is an integer from 0 to 2; A represents oxygen or a bond; Brepresents oxygen or a bond; R₃ and R₄ are hydrogen or methyl; or, whenm is 1, n and p are 0, A and B are bonds, and R₃ is hydrogen, R₄ canform with R₅ a methylene bridge —(CH₂)q- with q corresponding to 1 or 2,preferably 1; and R₅, R₆, R₇, R₈, and R₉, which are the same ordifferent, are each independently hydrogen, hydroxyl, C₁-C₄ alkyl, C₁-C₄alkoxy, halogen, SO₂NH₂, or 2-hydroxy-2-phenyl-ethylamino, or apharmaceutically acceptable salt thereof.
 4. Crystalline microparticlesaccording to claim 3 wherein R₁ is NHCOR₁₀, and R₂ and R₁₀ are H. 5.Crystalline microparticles according to claim 1, which are coated withsaid C12-C20 fatty acid in an amount of 0.5 to 2.0% by weight. 6.Crystalline microparticles according to claim 1, wherein said at leastone C12-C20 fatty acid is selected from the group consisting of lauricacid, myristic acid, palmitic acid, palmitoleic acid, stearic acid,oleic acid, arachidic acid, and a mixture thereof.
 7. Crystallinemicroparticles according to claim 6 wherein said at least one fatty acidis selected from the group consisting of myristic acid, palmitic acid,stearic acid, arachidic acid, and a mixture thereof.
 8. Crystallinemicroparticles according to claim 1, which have a [d(v,0.5)] of 1.5 to3.0 microns.
 9. A pharmaceutical aerosol formulation for a pressurizedmetered dose inhaler, comprising microparticles according to claim 1, insuspension in a liquefied propellant gas.
 10. A pharmaceuticalformulation according to claim 9, wherein said liquefied propellant gasis 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or1,1,1,2-tetrafluoroethane (HFA 134a), or a mixture thereof.
 11. Apressurized metered dose inhaler, comprising a canister containing anaerosol pharmaceutical formulation according to claim 9 and a meteringvalve for delivering a daily therapeutically effective dose of saidphenylalkylamino beta₂-adrenergic agonist.
 12. A dry powderpharmaceutical formulation, comprising microparticles according toclaim
 1. 13. A dry powder pharmaceutical formulation, comprisingmicroparticles according to claim 1 and a carrier.
 14. A process forpreparing microparticles according to claim 1, said process comprising:(a) preparing a solution of said C12-C20 fatty acid in a fluorinatedmodel propellant in which said beta₂-agonist is substantially insoluble,selected from the group consisting of perfluoropentane,2H,3H-perfluoropentane (HPFP), perfluorohexane, and 1H-perfluorohexane;(b) adding said beta₂-agonist as a micronized powder to said solution ofsaid fatty acid, to obtain a mixture; (c) mixing said mixture to obtaina homogeneous suspension; and (d) subjecting said suspension tospray-drying, to obtain coated microparticles.
 15. A process accordingto claim 14, wherein said fluorinated model propellant is2H,3H-perfluoropentane (HPFP).
 16. A method for the prevention and/ortreatment of a respiratory disease, comprising administering to asubject in need thereof an effective amount of microcparticles accordingto claim
 1. 17. A method according to claim 16, wherein said disease isasthma or chronic obstructive pulmonary disease.
 18. Crystallinemicroparticles, comprising of a phenylalkylamino beta₂-adrenergicagonist coated with a C12-C20 fatty acid in an amount of 0.2 to 2.0% byweight, based on the weight of said microparticles, which are producedby a process comprising: (a) preparing a solution of said C12-C20 fattyacid in a fluorinated model propellant in which said beta₂-agonist issubstantially insoluble, selected from the group consisting ofperfluoropentane, 2H,3H-perfluoropentane (HPFP), perfluorohexane, and1H-perfluorohexane; (b) adding said beta₂-agonist as a micronized powderto said solution of said fatty acid, to obtain a mixture; (c) mixingsaid mixture to obtain a homogeneous suspension; and (d) subjecting saidsuspension to spray-drying, to obtain coated microparticles.